Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition

Biphenylsulfonamido-3-methylbutanoic acids with potent activities in enzymatic and cell-based assays are presented. Design, synthesis and structure–activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 μg/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6 h and bioavailability of 23%.